![]() ![]() These findings support the novel combination of these drugs with currently available chemotherapies (e.g. Furthermore, this combination was more effective in cell lines with dysfunctional MGMT. This is highly related to the TGFβ signaling or cell cycle-modulatory effects of these agents. These studies indicate that timing of drug treatments strongly influences response to O6-Benzylguanine +Temozolomide plus TGF-β Kinase or CDK 4/6 inhibitor in MGMT+ glioblastoma cells. The interaction between the drugs was assessed. CDK 4/6 inhibitor has additional effects on cell cycling, including induction of an RB-associated G(1) arrest. Our in vitro data clearly demonstrate that TGF-β Kinase or CDK 4/6 inhibitors enhance O6-Benzylguanine + Temozolomide activity via disruption of TGF-β-dependent signaling and transcription or abrogation of the S and G(2) checkpoints. The LY compounds were developed by Lilly USA and are currently undergoing clinical trials testing safety and efficacy in treating several forms of cancer. ![]() Drugs included: MGMT inhibitors, LY2157299 (TGF-β kinase inhibitor), LY2835219 (CDK4/6 inhibitor) and Temozolomide in various combinations. This study used drug combinations in order to overcome this acquired resistance. Clinical studies have shown that some TMZ-resistant tumors have elevated MGMT protein levels or lack of MGMT promotor methylation. Resistance to this drug is modulated by the DNA repair enzyme methylguanine-DNA methyltransferase (MGMT). Implicated in this survival rate are cells that acquire resistance to Temozolomide (TMZ)-based therapy, the standard of care. Glioblastoma is the most common and aggressive form of brain cancer and demonstrates one of the worst five year survival rates of any cancer (3-8%).
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